Managed Approaches to Multiple Sclerosis in Special Populations

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that is classified as an immune-mediated inflammatory disease. In managed care, patients with MS can be managed through care coordination that engages an interprofessional approach to a comprehensive spectrum of preventive, medical, rehabilitative, cognitive, and long-term health care services. In addition, the management paradigm for MS is currently in a stage of rapid evolution, with a number of new agents, including more oral drugs, expected to become available in the near future. Pharmacy and therapeutic committees may soon be faced with evaluating a hierarchy of new scientific data to differentiate the safety and efficacy of these new agents. Decisions will need to be made regarding the utility of these potential new agents among existing therapies with longer-term safety and efficacy data available in the scientific literature. For those MS patients managed under Medicaid, formulary and medication management decisions may be further impacted by psychosocial, cultural, educational, attitudinal, and/or economic factors that may be unique to the Medicaid population. The need to maximize immediate and long-term resource utilization is usually an important consideration when managing a Medicaid population. There is also an increasing focus on quality measures and quality outcomes by the Centers for Medicare and Medicaid Services. Many managed care professionals can be involved in establishing quality measures and quality improvement processes to effectively appropriate and manage the resources required for Medicaid patients with MS. As a result, medication and medical management of this special population can involve a comprehensive approach by managed care professionals. For purposes of this article, the term “special populations” applies to patients with MS who are managed under Medicaid plans. OBJECTIVES: To review (a) particular challenges managed care organizations (MCOs) encounter when managing special populations of Medicaid patients with MS, (b) recent efficacy and safety data for oral therapies for relapsing forms of MS, (c) costs of current MS therapies, and (d) potential strategies for managed care to improve care of their MS patient population and optimize clinical and economic outcomes. METHODS: Review of recent published literature, abstracts related to MS presented at major medical conferences, and recommendations from key organizations including the U.S. Department of Health and Human Services and the National Multiple Sclerosis Society. SUMMARY: The health economics of MS are a central issue for MCOs managing Medicaid patient populations. Additional challenges include the anticipated expansion of the marketplace to include several new oral agents and the lack of consensus guidelines for management of patients with MS. The benefit-risk profile of new agents will need to be considered in the context of established first-line parenteral drugs. Management of patients with MS should include an individualized approach for each patient as part of a shared decision-making process. In the overall management of special patient populations, case management and collaborative practice models in managed care may help to ensure that critical benchmarks are achieved.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that is classified as an immune-mediated inflammatory disease. In managed care, patients with MS can be managed through care coordination that engages an interprofessional approach to a comprehensive spectrum of preventive, medical, rehabilitative, cognitive, and long-term health care services. In addition, the management paradigm for MS is currently in a stage of rapid evolution, with a number of new agents, including more oral drugs, expected to become available in the near future. Pharmacy and therapeutic committees may soon be faced with evaluating a hierarchy of new scientific data to differentiate the safety and efficacy of these new agents. Decisions will need to be made regarding the utility of these potential new agents among existing therapies with longer-term safety and efficacy data available in the scientific literature. For those MS patients managed under Medicaid, formulary and medication management decisions may be further impacted by psychosocial, cultural, educational, attitudinal, and/or economic factors that may be unique to the Medicaid population. The need to maximize immediate and long-term resource utilization is usually an important consideration when managing a Medicaid population. There is also an increasing focus on quality measures and quality outcomes by the Centers for Medicare and Medicaid Services. Many managed care professionals can be involved in establishing quality measures and quality improvement processes to effectively appropriate and manage the resources required for Medicaid patients with MS. As a result, medication and medical management of this special population can involve a comprehensive approach by managed care professionals. For purposes of this article, the term "special populations" applies to patients with MS who are managed under Medicaid plans. M ultiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that can result in long-term disability for patients with this disorder. Medicaid, Medicare Special Needs Plans (SNPs), and managed care organizations (MCOs) face especially challenging circumstances when working to manage the MS population as well as patients with other chronic conditions. Tools available to commercial insurers for Medicaid patients can be somewhat restricted in comparison to those available to the typical commercial insurer based on state and federal regulatory requirements. Members enrolled in Medicaid MCOs typically qualify for funded programs based on income and/or level of disability, among other indicators. Zero or minimum premiums, zero or minimal copayments, limitations on how aggressive MCOs can be when directing procurement and care through preferred providers, limitations on the ability to require the use of specialty pharmacy or community pharmacy in lieu of physician "buy-and-bill" all come into play when managing specialty products such as MS medications. State and federal requirements may also limit a health plan's ability to manage formulary options by placing restrictions on prior authorization requirements and even formulary content itself.
Many other factors impact outreach to special patient populations. Medical issues may become less of a priority when other concerns are present. Special populations frequently face other challenges such as concomitant behavioral health diagnoses, lack of education or understanding of their disease state, as well as other compounding social issues. In addition to these important considerations, the management of MS is currently in a dynamic phase in which several new disease-modifying therapies (DMTs), including relatively expensive oral agents, will need to be incorporated into the evolving MS management paradigm.

Approved and Emerging Oral DMTs for MS
In the last 2 decades, interferon (IFN) β-1 formulations and glatiramer acetate have become well established as first-line immunomodulatory therapies for relapsing forms of MS. 1 However, these agents must be administered by repeated subcutaneous or intramuscular injections, which can be a barrier for some patients, particularly those with "needle phobia," and lead to suboptimal long-term adherence/compliance that may influence clinical outcomes. 2 This is an important issue, as patients with MS will require a lifelong commitment to taking medications because MS is not currently considered curable. The immunosuppressive drugs natalizumab and, to a lesser extent, mitoxantrone are used as second-line (escalation) therapies in patients with MS; 3 however, these drugs must be given S4 Supplement to Journal of Managed Care Pharmacy JMCP November/December 2011 Vol. 17, No. 9-c www.amcp.org capsules. 6 In both studies, fingolimod was associated with significantly lower annualized relapse rates (ARR), the primary endpoint (Table 1). Among secondary endpoints, the proportion of patients who were relapse-free was higher with fingolimod compared with the control groups. Fingolimod treatment was associated with small effects on disability progression in FREEDOMS and no difference compared with the IFN active comparator in TRANSFORMS. The Expanded Disability Status Scale (EDSS) 7 scores at 24 months decreased or were unchanged for fingolimod in the 2 randomized controlled trials (RCT) compared with a small increase in the placebo group in FREEDOMS. Magnetic resonance imaging (MRI) outcomes were favorable for fingolimod compared with placebo and interferon. 5,6 Notably, there were no differences in efficacy outcomes between the 2 fingolimod dose groups (0.5 mg and 1.25 mg) in either FREEDOMS or TRANSFORMS, but the FDA approved only the 0.5 mg per day dose for fingolimod for "treatment of patients with relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability." 8 Key adverse events reported in FREEDOMS that were more common in the fingolimod 1.25 mg and 0.5 mg dose groups compared with placebo, respectively, included abnormal liver function tests (18.6% and 15.8%, vs. 5.0%), bronchitis (9.1% and 8.0%, vs. 3.6%), hypertension (6.3% and 6.1%, vs. 3.8%), lymphopenia (5.4% and 3.5%, vs. 0.5%), bradycardia/arrhythmia (3.3% and 2.1%, vs. 0.7%), pneumonia (1.9% and 0.9%, vs. 0.7%), and first-degree atrioventricular block (1.2% and 0.5%, vs. 0.5%). 5 Seven cases of macular edema (1.6%) were also reported in the fingolimod 1.25 mg per day dose group, whereas this event was not seen in the placebo or 0.5 mg fingolimod arms. Adverse events leading to discontinuation of medication occurred in 14.2% of patients in the 1.25 mg per by intravenous infusion under the supervision of a health care professional. As a result, there has been ongoing interest in developing effective oral agents for MS, which would be easier to administer and conceivably may remove the requirement for a visit to the doctor's office or clinic. The first oral medication for relapsing forms of MS, fingolimod, was approved by the U.S. Food and Drug Administration (FDA) in September 2010, and several additional oral agents are in late stages of clinical development. Oral MS drugs for which phase 3 clinical trial data are available are the primary focus of the discussion that follows.
Fingolimod. Also referred to as FTY720, fingolimod (Gilenya) is classified as a sphingosine-1-phosphate (S1P) receptor modulator. By binding to G-protein-coupled S1P receptors on lymphocytes, fingolimod inhibits the migration (egress) of autoreactive T cells from peripheral lymphoid organs into the bloodstream, thereby restricting their access to the brain and spinal cord where MS lesions occur. 4 The clinical efficacy and safety of fingolimod in patients with relapsing-remitting MS were evaluated in 2 large, randomized phase 3 trials known as FREEDOMS (Fty720 Research Evaluating Effects of Daily Oral therapy in MS) and TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RRMS). 5,6 Key efficacy data from these studies are summarized in Table 1. FREEDOMS was a 2-year, placebo-controlled study, whereas TRANSFORMS was a 1-year trial with an active-comparator (IFNβ-1a) arm; both studies evaluated 2 doses of fingolimod (0.5 and 1.25 milligrams [mg] per day). In TRANSFORMS, IFNβ-1a was given by intramuscular (IM) injection once weekly-thus, this trial had a design that included placebo injections for subjects randomized to the fingolimod groups, whereas patients in the IFNβ-1a arm took daily oral placebo with placebo (1.8%). Median lymphocyte counts reached nadir values at week 9 for the 3.5 mg per kg cladribine group and week 16 for the 5.25 mg per kg group. Gradual but modest increases in lymphocyte counts were seen, and at week 48, prior to initiation of the second dosing cycle, median lympocyte counts were -35.6% and -49.6% in the low and higher dose cladribine groups, respectively. Serious adverse events reported in the combined cladribine arms included herpes zoster infections (n = 20; 2.3%) and neoplasms (n = 10; 1.1%), whereas these events were not observed in the placebo group. 13 Cladribine was approved in 2010 in Russia and Australia for the treatment of patients with relapsing MS but was rejected by the European Medicines Agency (EMA) in a regulatory decision upheld in 2011. 14 A revised new drug application for cladribine for relapsing MS based on the CLARITY data was submitted to the FDA in June 2010. In March 2011, the FDA requested additional data on the safety and the benefit-harm ratio for cladribine, stating that while there was evidence for the clinical efficacy of this agent in relapsing MS, ongoing safety concerns (e.g., malignancies, viral infections) required a more complete understanding of cladribine's overall benefit-risk profile, either through additional analyses of existing data or new clinical studies. However, in June 2011, the pharmaceutical company developing this agent (Merck/EMD Serono) announced that they would no longer pursue the global approval process for cladribine as a treatment option for MS and would also remove this agent from the 2 markets (Russia and Australia) where the drug had been approved for use. 14,15 Teriflunomide. Teriflunomide is a selective reversible inhibitor of dihydroorotate dehydrogenase that blocks de novo pyrimidine synthesis in rapidly proliferating cells, including autoreactive T and B lymphocytes. 16 This oral agent is the active metabolite of leflunomide, an anti-inflammatory drug that is used in patients with rheumatoid arthritis. 17 Leflunomide is a prodrug with little or no immunomodulatory activity until nonenzymatic conversion to teriflunomide, primarily in the gut wall and liver. 18 Teriflunomide is undergoing evaluation in 6 phase 3 clinical trials for MS (HMR1726: NCT01252355, NCT00134563, NCT00622700, NCT00883337, NCT00751881, NCT00803049). 19 In the 2-year phase 3 TEMSO study (NCT00134563) of teriflunomide in patients with relapsing MS, patients were randomized to receive teriflunomide at a dose of 7 mg per day (n = 365), 14 mg per day (n = 358), or placebo (n = 363). 20 The ARR (primary efficacy endpoint) was 0.37 for teriflunomide 7 mg and 14 mg, relative reductions of 31.2% and 31.5% compared with placebo (0.54; P < 0.001 for both comparisons; Table 2). The proportion of patients with sustained disability progression (defined as an increase in the EDSS score of at least 1.0 point [or at least 0.5 points for patients with baseline EDSS score greater than 5.5] for at least 12 weeks) was lower for teriflunomide 14 mg day fingolimod group versus 7.5% for the 0.5 mg per day fingolimod group and 7.7% for placebo.

Managed Approaches to Multiple Sclerosis in Special Populations
The adverse events reported for fingolimod in TRANSFORMS were similar to FREEDOMS and included macular edema in 6 patients treated with fingolimod; 4 in the 1.25 mg dose group (1%) and 2 in the 0.5 mg arm (0.5%). 6 There was also an increased number of malignancies in the fingolimod 0.5 mg (n = 8) and 1.25 mg (n = 4) arms in TRANSFORMS compared with IFNβ-1a (n = 1), including basal cell carcinoma, breast cancer, and melanoma. 6 There were 2 fatal infections (disseminated primary varicella zoster and herpes simplex encephalitis) in the 1.25 mg fingolimod group. The product label for fingolimod currently recommends that all patients being considered for fingolimod therapy have a complete blood count, hepatic transaminase and bilirubin assays, electrocardiogram (ECG), and a baseline ophthalmologic examination prior to initiation of treatment. 8 Patients selected for therapy should also have their pulse and blood pressure closely monitored for 6 hours after the first fingolimod dose. 8 Ongoing clinical studies of fingolimod in MS include EPOC (ClinicalTrials.gov Identifier: NCT01216072), a phase 4 trial in which the active comparator group is enrolling patients who are currently using any of the available injectable IFNβ-1 formulations or glatiramer acetate.
Cladribine. The molecule 2-chlorodeoxyadenosine (cladribine) is a prodrug that requires phosphorylation to become an active purine nucleoside analog. Cladribine becomes highly activated within lymphocytes and makes them preferentially vulnerable to its cytotoxic effects. The accumulation of cladribine nucleotides leads to DNA strand breaks, interferes with DNA synthesis and repair, and ultimately results in lymphocyte apoptosis. 9-11 A parenteral form of cladribine is currently FDA-approved for the treatment of hairy cell leukemia. 12 Oral cladribine was evaluated in patients with relapsingremitting MS (n = 1,326) in the 96-week, placebo-controlled, phase 3 CLARITY (CLAdRIbine tablets Treating multiple sclerosis orallY) study. 13 In this trial, both cladribine doses (3.5 mg per kilogram [kg] and 5.25 mg per kg) or placebo were given in 2 or 4 short courses for the first 48 weeks, then in 2 short courses at week 48 and week 52 (for a total of 8 to 20 days per year). Significantly lower ARRs (0.14 and 0.15 vs. 0.33; P < 0.001), and higher relapse-free rates (79.7% and 78.9% vs. 60.9%; P < 0.001) were reported for the 3.5 mg and 5.25 mg cladribine groups versus placebo, respectively. There was also a reduced risk of 3-month sustained disability progression in the cladribine groups (hazard ratio [HR] = 0.67 and 0.69 vs. placebo; P ≤ 0.03) and reduced numbers of brain lesions on MRI scans (P < 0.001 for all comparisons). As expected, lymphocytopenia (as defined by Medical Dictionary for Regulatory Activities [MedRA]) occurred more frequently in patients receiving cladribine tablets (21.6% and 31.5% in the 3.5 mg per kg and 5.25 mg per kg dose groups, respectively) compared Laquinimod. Laquinimod is a derivative of linomide, a structurally related compound that had previously reached phase 3 studies in patients with MS, but whose clinical development was halted due to such adverse effects as serositis and myocardial infarctions. [21][22][23] Laquinimod, a pharmacologically and chemically distinct molecule, was selected based on structure/ function testing as well as efficacy and safety in experimental autoimmune encephalomyelitis (EAE) models. 24,25 Although the exact mechanism(s) of action of laquinimod is/are incompletely understood, this drug has been reported to (a) decrease secretion of proinflammatory cytokines and enhance secretion of antiinflammatory cytokines and (b) upregulate brainderived neurotrophic factor. 26,27 In addition, laquinimod was shown in an in vitro study to suppress genes associated with antigen presentation and inflammation in peripheral blood mononuclear cells from both healthy controls and patients with relapsing MS. 28 Laquinimod has been evaluated in 2 large, randomized phase 3 studies known as ALLEGRO (Assessment of oraL Laquinimod in prEventing proGRession Of MS; NCT00509145), which has a placebo control arm, and BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod; NCT00605215), in which the active comparator is IFNβ-1a 30 mcg per week. Neither the results from BRAVO nor ALLEGRO have been published in the peer-reviewed literature. Data from the ALLEGRO trial were reviewed in an oral presentation by Dr. Giancarlo Comi at the April 2011 annual conference of the American Academy of Neurology (AAN). 29 In ALLEGRO, patients were randomized to receive laquinimod at a dose of 0.6 mg per (20.2%) but not 7 mg (21.7%) compared with placebo (27.3%, P = 0.03 and P = 0.08, respectively). 20 Teriflunomide also significantly reduced disease activity measured by MRI outcomes, all of which were secondary endpoints in TEMSO. 20 For example, the burden of disease (total brain lesion volume) at 108 weeks was reduced by 39.4% (P = 0.030) and 67.4% (P < 0.001) in the 7 mg and 14 mg dose groups, respectively, compared with placebo. In both teriflunomide dose groups, there were also significantly fewer T1-gadolinium (Gd) enhancing lesions per scan (P < 0.001) and higher percentages of patients who were MRI-lesion free (51.4% and 64.1% in the 7 mg and 14 mg active treatment arms, respectively) relative to controls (39.0%; P < 0.001). Teriflunomide did not have a significant effect on brain parenchymal fraction (atrophy), also a secondary outcome, over the course of this study (Table 2). 17 Teriflunomide was generally well tolerated, with a similar number of patients reporting serious treatment-emergent adverse events in the active treatment and placebo arms. Adverse events occurring at higher rates in the 7 mg and 14 mg teriflunomide groups compared with placebo, respectively, included diarrhea (14.7% and 17.9% vs. 8.9%), nausea (9.0% and 13.7% vs. 7.2%), elevated alanine aminotransferase (ALT) activity (12.0% and 14.2% vs. 6.7%), and mild hair thinning or hair loss (10.3% and 13.1% vs. 3.3%). 20 Elevated ALT levels at least 1 times the upper limit of the normal range occurred more often in teriflunomide patients (54.0% and 57.3% for 7 mg and 14 mg, respectively) compared with 35.8% of control patients, but there was no significant difference among the 3 groups for ALT elevation at least 3 times the upper limit of normal (6.3%, 6.7%, and 6.7%, respectively). There was a similar incidence of serious infections in the 3 study arms (2.2%, 1.6%, and 2.5% for teriflunomide 7 mg and 14 mg, and placebo, respectively). population. 34 The prospect of being able to administer a drug orally rather than by sometimes painful injections is a desirable option for these patients. Oral dosing is also more convenient for both patients and caregivers, although this may not necessarily translate into improved adherence.

Managed Approaches to Multiple Sclerosis in Special Populations
As with all formulary decisions, it is important to first review the overall profile of new products and, as applicable, compare this with existing drug entities. As noted previously, patients who receive fingolimod must undergo additional screening prior to therapy initiation as well as ongoing monitoring during treatment. 8 This includes evaluations of cardiac function as fingolimod is associated with both bradycardia and atrioventricular block. 5,6 These steps are not required with the established platform (first-line) agents for MS. Added costs associated with ECG and additional billing of associated physician services should be evaluated and calculated. Avoidance of visits to physician offices or ambulatory care centers for infusion therapy, such as is necessary when natalizumab is prescribed, may ease the patient's burden of administration and decrease costs spent by the MCO for physician or outpatient services.
Information provided by the pivotal clinical trials on new oral agents is an important evaluation tool, but the length of these studies must also be taken into consideration. Additional data are needed from long-term trials as well as direct comparison studies so that these data can be utilized when evaluating novel products. It should be noted that an extension analysis of the TRANSFORMS study of fingolimod was recently published, with no new unexpected safety concerns reported. 35 Because the peak age of onset of MS is between 20 to 40 years, there is a high likelihood of women being within their child-bearing years, 36 making a medication's pregnancy safety status an important factor when reviewing for formulary inclusion. It should be noted that symptoms associated with MS tend to be reduced or masked during pregnancy, which has led to the hypothesis that estrogen may play a role in prevention of MS progression. 37 Fingolimod and the other MS agents, with the exception of glatiramer acetate (Category B) are classified as Category C with respect to fetal risks. 8,37 However, none of the DMTs are approved for use during pregnancy. It should be noted that risk/benefit decisions are still made between physician and patient when pregnancy factors into the treatment plan, and women who are taking any medications for MS should discuss their plan to become pregnant with their prescribing physician.
Based on the properties associated with each individual drug entity, MCOs must make informed choices for the populations they serve. The opinions and practice patterns of national, regional, and local specialists must become a key piece of the evaluation process for newly approved drugs. As practice guidelines and practice patterns are developed and updated, MCOs must continue to evolve with their approved drug offerings to most appropriately serve the lives that they day (n = 550) or matching oral placebo (n = 556). For the primary efficacy endpoint, laquinimod treatment was reportedly associated with a 23% reduction in the ARR compared with placebo (RR = 0.77; P = 0.002), with absolute rates of 0.304 for laquinimod versus 0.395 for placebo. Among secondary endpoints, the risk for disability progression, sustained for at least 3 months as measured by EDSS scores, was reduced by 36% in the laquinimod arm (HR = 0.641; P = 0.012); the absolute rates were not reported. Progression of brain atrophy was reportedly reduced by 32.8% in laquinimod-treated patients (P < 0.001); the absolute rates were not reported. Adverse events that were more common in the laquinimod arm compared with placebo included ALT elevations (6.9% vs. 2.7%), most of which were more than 3 times the upper limit of normal (4.9% for laquinimod vs. 2.0% for placebo); ALT elevation was responsible for treatment discontinuation in 13 laquinimod versus 7 placebo patients. Other adverse events that were more common with laquinimod included abdominal pain ( Other Oral Agents for MS. At least 2 additional diseasemodifying oral agents for relapsing forms of MS are currently being evaluated in phase 3 studies: dimethyl fumarate (BG-12) 30,31 and firategrast. 32 Firategrast is an antagonist of alpha 4 integrin, the same molecular target as the monoclonal antibody natalizumab currently approved for treating MS. However, because the phase 3 data for these agents were not published or presented at the time of preparation of this article, these 2 agents will not be discussed further.

Risk-Benefit Decisions with New Oral Agents for MS
The availability of new oral agents for relapsing forms of MS provides both opportunities and challenges for patients, providers, caregivers, and MCOs, and additional oral DMTs are expected to become available in the near future.
Prior to the approval of oral fingolimod, first-line or "platform" treatment options for relapsing forms of MS consisted of the IFNβ-1 preparations and glatiramer acetate. These medications, which are all administered by injection, have essentially equivalent efficacy in terms of reducing relapse rates and slowing disease progression. 33 Despite some injection-site reactions (e.g., erythema, edema, inflammation, pain, itching) and potential post-injection systemic effects (e.g., nausea, flu-like symptoms, flushing, chest tightness), the IFNs and glatiramer are recognized to be relatively safe with few major long-term associated risks. In addition, health care professionals generally have extensive experience with and are relatively comfortable with these agents. However, some patients simply do not like to take injections, which can negatively impact adherence. 2 Needle phobia has been reported in up to 22% of the general outpatient clinics or other high volume facilities. In addition, the level of MS expertise varies, and the clinical focus may not include prevention of secondary complications. The opportunities for effective patient education in these settings may be limited, and some ethnic groups may encounter barriers when communicating with physicians or finding written information in their native language. When DMTs for MS are considered appropriate, patient education is an important factor not only in the choice of agent, but also with subsequent adherence/ compliance with the prescribed medication. Therefore, specialist contact and effective patient education are important components of a successful ongoing management strategy for patients with MS. 46 When individuals with complex chronic diseases from lowincome minority groups experience challenges in accessing appropriate health care, suboptimal care and outcomes may result. As part of a performance improvement study, Shabas and Heffner (2005) described the conduct of a survey to evaluate the impact of cultural and socioeconomic factors on the quality of care for low-income minorities with MS enrolled in Independence Care System (ICS), a Medicaid long-term managed care plan for people with physical disabilities in New York City, where 89% of members were from minority groups (primarily African Americans and Hispanics). 46 The lack of private insurance and minimal financial resources was cited as a factor in limiting ICS-member options for receiving specialty care. Care management teams, which included a social worker and a nurse dedicated to each ICS member, coordinated health care services. This study concentrated on 3 aspects of MS care: (1) contact with an MS specialist, (2) treatment and compliance with immunomodulatory medications, and (3) osteoporosis screening, prevention, and treatment. Several deficiencies were identified in the care of the low-income minority population with MS in each focus area. Of those surveyed, 32% were never examined by an MS specialist, and approximately one-third were not taking immunomodulatory medications, primarily due to noncompliance caused by a lack of understanding about these drugs (presumably due to inadequate education). The prevention of osteoporosis and potential fractures in this high-risk patient population, of whom 32% were 50 years of age or older, was generally neglected by providers, even though most survey participants also reported balance difficulties and a prior history of falls. The authors concluded that education regarding the importance of prevention of osteoporosis, fall mitigation, and rehabilitation evaluations were important strategies to decrease fracture risks in this population. 46 As an outcome of this ICS performance improvement project, a set of MS care guidelines and interventions was established to address the identified deficiencies. 46 These focus primarily on education, are consistent with published recommendations, and can be replicated at other MCOs for members diagnosed with MS. For example, information cover. This will require ongoing evaluation as new oral drugs for MS enter the marketplace. In addition, careful assessment of the risk/benefit profile of the various agents for relapsing MS should include an individualized approach for each patient as part of a shared decision-making process. 38,39 MS Policies and the Underserved MS is a chronic disease that currently is not curable and must be managed with a comprehensive spectrum of preventive, medical, rehabilitative, mental health, and long-term care services to assist affected individuals and their families. Thus, in 2008 the National Multiple Sclerosis Society adopted the 7 National Health Care Reform Principles to shape policies and facilitate change. 40 Published reports have indicated that a significant proportion of patients with MS discontinue or interrupt treatment with DMTs. For example, up to 27% of individuals discontinued within the first 6 months of MS therapy initiation. 41 In another sample of newly diagnosed relapsing MS patients starting DMT, 43% became nonpersistent within 14 months. 42 One of the primary reasons cited in studies of therapy interruption is the perceived lack of clinical efficacy, often associated with unrealistic treatment expectations. 43 Policies such as requirements for prior treatment authorization, "tiered" benefits, and restrictive refill policies may limit access to drugs. 44 Generic equivalents, which might reduce costs, are not yet available for the relatively expensive DMTs approved for patients with MS. For those requiring additional medications for other MS-related symptoms, including ataxia, spasticity, pain, and bladder or sexual dysfunction, significant additional drug expenditures may be incurred. Neurologists and their treatment teams are usually required to fill out extensive paperwork to gain patient access to these programs and to provide prior authorization to health care insurers. 44 In a survey conducted by Iezzoni and Ngo (2007) 45 Additional challenges in receiving optimal health care are faced by individuals from lower-income minorities who have physical disabilities. These patients may face architectural, transportation, and attitudinal barriers with the additional potential impact of cultural and socioeconomic factors on health care quality. 46 Many minority patients who live below the poverty level, particularly women, receive care in hospital (ALOS) in year 1 were significantly shorter (6.23 days) compared with ALOS 1 year prior to program enrollment (11.13 days; P = 0.017), suggesting that these services facilitated earlier discharge to home health nursing care. 49 As initially proposed by the Institute of Medicine, 50 DCCOs contract with state Medicaid programs and MCOs to arrange or provide disabilitycompetent health and social services. DCCOs typically assign a nurse or social worker to each enrollee, who collaborate to develop an individualized management plan and then interface with patients to ensure that services are appropriately provided as needed. These services include physical, dental, and mental health care; prescription and acquisition of assistive technologies and durable medical equipment; deinstitutionalization; accessible transportation; access to community services; and subsidies for utility bills. 49 What strategies might be employed to improve access to care for individuals with MS as well as the equity of payment to their health care providers? One possible solution to the lack of adequate payments for the care of enrollees with MS is to further adjust premiums and capitation payments for the diagnoses of plan members-so-called diagnostic risk adjustment. One of the most promising approaches to fair compensation for the medical care of MS may be supplementing this strategy with functional status measures, if possible. Pope et al. (2002) found that costs were 2-3 times higher for insured enrollees with MS compared with average insured members. 51 For example, calculated annual all-cause medical expenditures were estimated as $7,677 per privately insured enrollee with MS versus $2,394 for all privately insured enrollees, $13,048 per Medicare beneficiary with MS compared with $6,006 for all Medicare beneficiaries, and $7,352 per Medicaid disabled recipient with MS versus $4,088 per disabled recipient without MS. The results of this analysis identified 2 important implications: (a) despite the tendency to under-identify persons with MS in claims data, MS prevalence rates are actually higher than anticipated; and (b) MS patient access to care and appropriate capitated payment levels to care providers must be adequate. Importantly, if the premiums that employers or governments pay insurers and the capitation amounts that insurers pay health care providers do not account for these higher costs, a disincentive may be created for the enrollment and care of persons with MS. Further supplementing diagnostic-based risk adjustment with functional status measurement identifies and directs greater resources to the most disabled and highest-cost patients with MS. A complete carve-out of MS-related services represents another possible approach to provider reimbursement for care. 51 As MS is a chronic, disabling, and potentially progressive disease, programs that promote symptom management, medication adherence, and a health-promoting lifestyle are important in the overall management of MS. One example of a disease therapy management (DTM) program that incorporated regarding immunomodulating agents and osteoporosis prevention in both English and Spanish is provided to all members, and referrals to an MS specialist are arranged for those who have never been evaluated by one. All members at increased risk for falling are referred to a rehabilitation professional for an evaluation as part of a falls prevention program. Wheelchair users who transfer independently are now evaluated for the safety of their technique. 46 This strategy to improve MS care for this patient population is consistent with a disease management/case management approach that involves coordination of care through close collaboration among the patient, treating practitioners, and the interprofessional managed care team. These programs incorporate evidence-based practice guidelines and a set of interventions to optimize patient care and focus on patient education, as well as support systems to assist providers in monitoring patients and helping them adhere to their prescribed medications. Elrod and DeJong (2008) reported that patients with lower household incomes and poorer health status were less likely to receive physical rehabilitation services. 47 These findings highlight the disparities between health plans in their ability to meet plan participants' needs. Additionally, the medicalnecessity criteria of payers often require that services be inherently restorative in order to be considered a reimbursable service. Since therapy that minimizes progressive loss of function may not necessarily improve function, policymakers and health plan administrators should re-evaluate their criteria for coverage of physical rehabilitation services. Optimal design should enhance quality of life and reduce the burden of lost independence. Future policy discussions should focus on how to address potential gaps in health plan coverage that may compromise clinical outcomes, productivity, and quality of life for patients with chronic conditions such as MS. Longitudinal analyses may also be useful in identifying persistent service gaps and how these may affect health outcomes. 47 In an additional analysis focusing on minorities, African-American (AA) MS patients exhibited a more rapid decline in cognitive function than a non-AA comparator group. 48 Medicaid is the primary insurance provider for AA patients in the New York State MS Consortium registry, and the proportion of this subpopulation in the consortium is relatively low (6%). Notably, there were no differences seen in this study in the types of MS or the use of DMTs in the 2 patient populations. However, AA patients were more likely to develop greater physical disability with increased disease duration. These findings from Weinstock-Guttman et al. (2003) in this minority subpopulation suggest that MS is more aggressive in AA patients and that they may be at higher risk for progression of disability than non-AA patients. 48 In a study by Palsbo and Diao (2010) evaluating a disability care coordination organization (DCCO), while hospital admission rates were unchanged for enrollees, average lengths of stay MS, the use of physical therapy (PT) and occupational therapy (OT) was significantly associated with the payment source, suggesting that when reimbursement was available, the specific service was more likely to be prescribed or requested. 64 Rehabilitation efforts can potentially be confounded by comorbidities such as weakness, spasticity, cognitive dysfunction, and sensory symptoms. 65 As provision of rehabilitative services can be expected to lessen the impact of disability, expanded Medicaid coverage may reduce overall long-term health care costs and improve patient quality of life. 64 Consistent with other published literature, MS residents with Medicare or private health insurance were more likely to receive PT or OT, while self-payers or those with Medicaid or VHA coverage were less likely to receive these therapies. Additional outcomes research is needed to evaluate the effects of rehabilitation therapies on the physical dependency and cognitive ability of nursing home residents with MS. 64

MS Medication Safety and REMS
The consequences for failing to meet medication safety expectations can lead to possible regulatory sanctions and exposure to liability. 66 Recognizing that certain drugs may be unsafe when used without precautions or restrictions, the FDA Amendments Act (FDAAA) became law in September 2007 (PL 110-85). One of the most important components of the FDAAA was the establishment of formalized risk evaluation and mitigation strategies (REMS) to guide the safe prescribing, dispensing, administration, and monitoring of potentially problematic drugs. 66 Components of individual REMS may vary but generally include medication guides, informed consent forms, laboratory monitoring for effective and safe initial and ongoing use (e.g., normal test results), restricted distribution/dispensing/ settings, specialized training/certification/experience, specific ordering/inventory procedures, patient registries, and prescription stickers. 67 With several new MS therapies anticipated over the next several months and years, it is unclear whether and to what extent REMS requirements will be associated with these new approvals. The safety of newer therapies will likely be questioned and compared with the relatively well-established safety data for traditional parenteral DMTs. Under the current REMS program, however, MCOs may not find substantial assistance in evaluating new MS drugs. Therapies are initially evaluated for safety by an MCO based upon data from the initial clinical trials. Once the drug is used commercially, additional safety information may emerge, but REMS assessment reports are only required after 18 months, 36 months, and 7 years.
Importantly, the goal of REMS is to ensure that the benefits of a prescribed drug outweigh the associated risks and that these risks are appropriately communicated and mitigated. 67 Elements of the REMS applied to emerging MS therapies might both self-management and medication therapy management components within a structured 7-month program was evaluated by Stockl et al. (2010). 52 This DTM program was reported to (a) significantly increase adherence to injectable medications for enrolled patients compared with community pharmacy patients (0.92 vs. 0.86; P < 0.001); (b) significantly improve persistence on therapy for both community (220 days vs. 177 days; P < 0.01) and specialty pharmacy patients (200 days vs. 188 days; P = 0.002); and (c) decrease the incidence of MS relapses from months 0 to 6 (14.0% vs. 9.1%; P = 0.03). The MS DTM program did not result in improvement in health-related quality of life or work productivity, but patients reported that the program enabled them to improve management of their health. 52 Studies on adherence to injectable MS therapies have reported that approximately 80% of MS patients adhere 80% of the time for the first 6 months, 53 but that only 60% to 76% adhere to therapy for 2 to 5 years. 43 Problems with injections, perceived lack of efficacy, and side effects have been identified as major barriers to long-term adherence in patients with MS. 54 MCOs have an interest in clinical programs that can reduce the higher medical expenditures incurred by MS patients. 52 A condition management program for MS described by Tan et al. (2010) was associated with improved medication adherence and persistence, reduced MS-related hospitalizations, and decreased MS-related medical costs. 55 However, the authors concluded that the cost savings in the medical component (-$264) during the 12-month follow-up period did not offset the increased pharmacy expenditures for MS drugs (+$2,184). Interventions included direct mailing of medication and disease-specific patient education materials to patients, including refill reminder calls. 55 Previous studies have demonstrated the feasibility of MS management programs for patient education, exercise, depression, and energy conservation in patients with MS. [56][57][58][59] Approximately 20% to 25% of MS patients will require long-term care during their disease course, and approximately 5% may eventually need care in an assisted living or nursing facility. 60,61 Nursing home residents with MS represent a unique population subset, differing in a number of ways from most other residents. 61 Many state Medicaid programs use flatrate payment schedules that do not adjust for the care needs of individual residents, thus providing incentives to nursing facilities to limit the number of residents receiving rehabilitation therapies and minimizing financial incentives to provide these services to admitted patients. 62 Other state Medicaid programs utilize case mix payments to reimburse nursing facilities, which theoretically links the payment level to the facility's cost of providing care to residents. 63 Nursing home residents who have Medicare coverage are eligible for skilled rehabilitation services if these are required to improve or maintain their condition and prevent deterioration. 62 In a publication by Buchanan et al. (2006) evaluating nursing home residents with that a case management program for MS could improve outcomes, increase compliance, and reduce long-term disability. 77 Further, patient education provided through case management/disease management services received the highest ranking (90%) as a value-added pharmacy benefit. 76 Case management is a tool often used by MCOs to manage the triad of access, quality, and affordability surrounding patient care. Among the standards of practice for case management is the responsibility to track and measure interventional outcomes that include treatment-related cost-savings. 72 Not only are the numbers of new product options, including oral agents, growing in the MS arena, but the price of specialty drugs is increasing at approximately twice the rate of other outpatient pharmaceuticals. While protein-based ("biologic") medications are evaluated in fewer numbers of subjects in clinical trials than small-molecule drugs, and rates of FDA approval are generally higher for biologic agents, these factors do not result in lower prices for the biologic agents. 78 The cost of DMTs for relapsing forms of MS is an issue of ongoing concern. One study by Kobelt et al. (2006) attributed 22% of the total costs and about 48% of the direct costs of MS care in the United States to DMTs. 79 Remaining total costs were divided among informal care (12%), absenteeism from work (10%), other drugs (6%), technology adaptations (5%), ambulatory care (4%), hospitalization (3%), services, and diagnostics (2% each). The largest total cost driver was identified as forced early retirement (34%). In all, 64% of costs were attributed to direct costs and 37% to indirect costs. The overall cost of MS care was estimated at $47,215 per person, per year, in 2004 U.S. dollars. 79 In a similar analysis of MS costs, Prescott et al. (2007) found that 64.8% of total costs were attributable to the cost of prescription drugs and 61.4% to the cost of DMTs. 80 Notably, the annual average wholesale price (AWP) of fingolimod ($56,909), the first oral agent approved for relapsing forms of MS, is significantly greater than the cost of the firstline injectable drugs. 81 Current evidence pertaining to the total economic impact of DMTs for MS is variable and is influenced by factors such as contracting arrangements and benefit design that includes variables such as pre-authorization criteria and tiered copayments. As a result, all direct and indirect costs associated with MS management should be considered when considering strategies to improve outcomes for patients with MS.
In the wake of MS costs, Medicaid managed care and virtually all MCOs impacted by MS seek methods to lower costs and reduce administrative overhead, while measurably improving quality of care and patient outcomes. Among tools in the toolbox for pharmacists and case managers are process metrics and outcomes metrics to evaluate and manage patients with MS. Assessment of outcomes provides the framework for future planning, and careful and accurate assessment of outcomes of interventions will improve the ability to assist MS patients include a combination of medication guides; patient package inserts; communication plans for health care providers; and specific requirements for prescribers, dispensers, and users of novel therapies. 68,69 Opportunities to Apply Case Management to MS While patient safety is managed at the system level through REMS, individualized patient safety, as well as adherence, can be managed through collaborative practice strategies engaged at the MCO level among pharmacists, case managers, and physicians. A study conducted among Iowa Medicaid patients taking multiple medications to treat chronic conditions demonstrated that improvements in drug therapy can be achieved from collaborative practice between physicians and pharmacists. 70 Although this study defined a case management model of pharmacists and physicians in medication therapy management in the community setting, case management programs in MCOs typically involve nurse case managers. Among these models, collaboration between nurse case managers and pharmacists is increasing as the pharmacy management needs become more complex. 71 Case management is defined as a collaborative practice model of assessment, planning, facilitation, care coordination, evaluation, and advocacy for options and services to meet an individual's and family's health needs through communication and available resources to promote quality, cost-effective outcomes. 72 In Medicaid managed care, nurse case managers could be utilized to coordinate options and services for MS patients with an intended goal to maximize both clinical outcomes and resource utilization. This may involve collaboration with managed care pharmacists to educate patients about compliance. As noted previously, one frequent reason patients with MS cease taking their medications is a perceived lack of clinical efficacy, requiring reinforcement education. 43,73 At every level of intervention, MS patients appear to fit the criteria for case management services. Although the estimated prevalence of MS is relatively low-affecting approximately 400,000 persons in the United States, with 200 people newly diagnosed weekly, according to the National Multiple Sclerosis Society 74 -annual treatment costs for this patient population are in the billions of dollars. 75 MS is a long-term, slowly progressive condition with clear, measurable outcomes affecting a relatively small number of individuals while generating high expenditures, but with a reasonable clinical return on investment. Because MS is not highly prevalent in the general population, less than 10% of MCOs surveyed in 1 study stated that they offered fully developed case management programs that incorporated reporting and clinical outcome tracking capabilities for this disorder, and an additional 27% did not track the number of members who were diagnosed with MS. 76,77 This may represent an unmet need that is prime for development based on the fact that more than two-thirds of MCOs agreed under the guidance of algorithms, standards of care, clinical guidelines, and institutional or organizational protocols pertinent to the patient's clinical condition. In the absence of clinical guidelines for treatment and management, such as in MS, case managers rely on health assessment screening tools and functional outcomes, such as the Kurtzke EDSS. 7 Variances from protocols are tracked as "outliers" and identified as being caused by the patient, provider, or system. Outliers can be common among MS patients in Medicaid populations, and causes are often patient-related. 87

Strategies to Optimize Costs of Drugs Used for Relapsing MS
The economic burden of MS exceeds debilitating diseases occurring later in life, such as Alzheimer's disease or stroke because of the young age of diagnosis, with approximately 75% of cases diagnosed between the ages of 20 and 50. 36 Advances in validated MRI measures of MS disease activities have led to changes in the diagnostic criteria of MS, resulting in more accurate and earlier diagnosis for many patients. 88 The majority of individuals with MS will live a normal life span. 89 Several DMTs were developed in the 1990s and were found to significantly reduce the number of relapses and progression of the disease. 33 Goodin et al. (2011) in a poster abstract reported data from 21 years follow-up of patients previously treated with an IFNβ-1b for MS. 90 Those patients originally randomized to IFNβ-1b 250 mcg had a significant reduction in all-cause mortality of 46.8% (proportion of patients deceased at 21 years was 32.3% for placebo vs. 20.5% for IFNβ-1b; HR = 0.532, P = 0.017). 90 This is one of the first long-term studies to support a significant reduction in all-cause mortality. With the release of this long-term data and the potential for these results to be extrapolated to other medications in the interferon class (e.g., Rebif and Avonex), economic analysis of DMTs is necessary. Asche et al. (2010) analyzed the health care utilization and costs associated with newly diagnosed MS patients (over the initial 12 months after diagnosis) compared with otherwise healthy patients with similar demographic and other variables (e.g., region, insurance type, gender, age, and enrollment period). 91 Total all-cause health care costs for MS patients, over a 12-month post-index period, were 4.7 times the cost for health comparison patients ($18,829 vs. $4,038, P < 0.001), with 7.5-fold higher pharmacy costs. 91 The economic evaluation described previously by Kobelt took into account both direct costs (inpatient and ambulatory care, prescription medications, and other services) and indirect costs (e.g., lost workplace productivity). 79 Annual costs increased from an average of $32,297 for patients with EDSS scores less than 4.0 (normal neurologic exam to mild or moderate disability) 7 to $64,492 for those with EDSS scores greater than 6.0 (walking assistance needed to complete dependence). 7 in establishing short-term and long-term goals. Managed care pharmacists and nurse case managers have the responsibility to identify and utilize meaningful outcome measures. Thus, it is important that each intervention has a planned outcome as well as the methodology to evaluate that outcome. 82 The National Multiple Sclerosis Society suggests that the factors that must be considered when making the decision to treat are complex and perhaps best analyzed by the individual patient's neurologist. Therapy is usually continued indefinitely, except for the following conditions: (a) there is clear lack of benefit, (b) there are intolerable side effects, and/or (c) better therapy becomes available. The society urges that payers make these therapies available as early as possible in the disease process. 83 In order to measure the outcomes of MS interventions in managed care, and particularly among special populations, there are a number of strategies that may be utilized. Baseline claims data can be gathered, including clinical information, population demographics, and costs of care. Costs of MS care will typically include diagnostics, medical and pharmacy costs, and utilization, including under-and over-utilization of services. Outcomes obtained through case management interventions can also be provided, including intangible effects to augment clinical outcomes data and demographic analyses.
Descriptive and demographic statistics of value in MS outcomes can include age, sex, socioeconomic status, disease severity, and disease burden. Operational statistics may be useful to determine the impact of MS in a plan and could involve such measures as the cost of MS patient support and medical care coordination provided through the nurse case manager or time spent by the pharmacist providing reinforcement education in medication adherence. Statistics may also include the number of prescriptions filled by drug and class or costs per patient and per drug. Clinical statistics used to measure the outcomes of MS management may include adherence statistics; risk assessments, such as depression screenings; or comparative data of the percentage of drugs that met utilization criteria versus exception to benefit reports.
Outcomes measurement is a core function of case management, and case management has been established as having a positive impact on outcomes management in special populations. Bender and Nancee (2003) have previously identified the effectiveness of case management in monitoring patient outcomes within a Medicare population. 84 Another study substantiated the effectiveness of nurse case managers in improving the health outcomes among patients with common chronic diseases impacting managed care: diabetes, COPD, and coronary artery disease. 85 The significant role of nurse case managers in transitions of care, and their affect on outcomes of transitions of care, has been substantiated by Cotter et al. (2002). 86 Outcomes measurement in transitions of care require case managers to coordinate services and health care providers be preserved. Once the patient has tried preferred DMTs and has met the prior authorization criteria associated with those, MCOs may place online step-therapy requirements on nonpreferred products requiring trial and failure or intolerance to the preferred products.
Step-therapy criteria may be placed on those products that are second-or third-line therapies. Products for which there are higher incidences of adverse events and/or minimal long-term efficacy and safety data associated with therapy have nonpreferred status.
MCOs utilize pharmacy and therapeutics (P&T) committee meetings to review products for inclusion on formulary based on medication safety, efficacy, and economic data. MS outcome measures that over 50% of MCOs identify as impacting coverage and formulary decisions for MS therapies include decrease in disease progression and severity, decrease in hospitalizations and other health care costs, follows health plan guidelines, reduction in adverse reactions, and improved adherence and persistency. 98 When products are new to a drug class, they are compared with the commercially available products and current formulary offerings. If there are no specialists on the P&T committee to provide expert opinion, the MCOs will typically invite a specialist to the meeting or elicit input from the specialists prior to the meeting so that committee members can make an informed decision for formulary inclusion.
Once a formulary decision is made, MCOs may decide if a medication should be obtained through a specialty pharmacy provider (SPP). Specialty drugs may be defined as high-cost injectable, infused, oral, or inhaled drugs that generally require close supervision and monitoring of the patient's drug therapy. 99 Specialty drugs fall into 2 categories based on the site and method of administration: (1) that are administered by either the patient or caregiver and (2) those that require a health care professional to administer them in a physician's office, infusion center, outpatient hospital department, or home. The majority of MCOs include self-administered injectables in the pharmacy benefit. Those injectables requiring office administration may be obtained by physicians who submit claims for reimbursement; this process is commonly referred to as buy and bill. 99 Many MCOs find it challenging to control the management and costs of these medications when there are different options for dispensing and reimbursement.
SPPs oversee the distribution, management, and reimbursement of specialty pharmacy products, typically at a discounted rate. Industry trends have shown increasing utilization of SPPs, with 70% of surveyed MCOs mandating the use of SPPs for MS products "always or frequently." 100 Efficient distribution systems, ancillary care, and case or disease management services are some of the benefits of utilizing an SPP. SPPs may disseminate disease-and patient-specific education materials, provide telephonic intervention and care coordination between providers and the patient, provide counseling and assistance in coordination of benefits and reimbursement, monitor different relapse severities. 92 Treatment for a relapse requiring low-intensity care averaged $243 per relapse; medium intensity treatment averaged $1,847 per relapse; and high-intensity care averaged $12,870 per relapse. 92 The large differential in the cost of relapse severity suggests the need to evaluate the costeffectiveness in preventing relapses with DMTs.
Clinical effectiveness of DMTs in RCTs typically focuses on the number of relapses avoided. These data, along with the estimated cost of a relapse, can be utilized to determine the cost of relapse avoided. In June 2011, Becker and Dembek 93 provided a revised economic model for cost-effectiveness based on the original 2009 Goldberg et al. study. 94 Becker and Dembek focused on the 2-year cost-effectiveness of the 4 parenteral DMTs used as first-line options for relapsing-remitting MS. Utilizing data from randomized studies, they reported the number of relapses that could be avoided for 2 years using IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC, and glatiramer acetate SC were 0.74, 0.75, 0.71, and 0.67, respectively. 93 Total MS-related costs for IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC, and glatiramer were $57,995, $59,916, $61,733, and $59,044, respectively. This provided a cost per relapse avoided of $77,980, $80,121, $86,572, and $87,767, respectively. 93 As described by Bell (2011), economic modeling of the DMTs for MS is fraught with many challenges that put even the best cost-effectiveness analysis practice guidelines to the ultimate "stress test." 95 Because there may be numerous methodological issues in developing economic evaluations and conducting cost-effectiveness analyses, they must be carefully designed and tested to ensure accurate results and appropriate interpretation of those results. 95 MCOs may utilize these studies as a guide when conducting their own internal analyses of their MS patient population.
As patients with MS progress, there is a linear progression of direct and indirect costs associated with their care. MCOs may have little impact on the control of the indirect costs and tend to streamline their focus on how to impact direct costs. Currently, there are no DMTs available in the generic form, with the first, glatiramer acetate, not likely to appear until 2014 at the earliest. 96 Because of this, many MCOs rely on formulary management tools to control pharmaceutical costs. Edlin and Sonnenreich (2011) surveyed 109 individuals directly involved with formulary management within MCOs. 97 On average, 50% of MCOs utilized prior authorization to manage the DMTs for MS; 47% limited use to FDA-approved indications; 28% set limits on the quantity; and 18% used step therapy. 97 Other data from 93 health plans reported in the 2011 EMD Serono Specialty Digest showed that 65% of health plans had preferred MS products, 55% used national drug code (NDC) number lock-out or prior authorization; 42% used tiered copayments; and 32% used online step-therapy edits to manage the DMTs. 98 MCOs may have preferred DMTs on the formulary with prior authorization criteria focusing on the appropriate diagnosis in patients in which there is functional status that can  101 The Medco Health Solutions 2011 Drug Trend Report stated that drugs used to treat MS are second only to rheumatologic drugs as the primary drivers of compliance, coordinate nursing and social work support networks, coordinate patient assistance programs, and provide assistance with clinical management of disease state programs. 101 An MCO with resources to provide MS case management services to their members may also utilize the SPP's contact with the patient for monthly delivery to allow for care coordination between the health plan and the patient. Many questions asked at the time of refill by SPPs may trigger an outreach call from a member of the MCO's case management team, who may follow the member until his/her condition is stable.
While SPPs provide many benefits to help manage patients with chronic diseases requiring specialty medications, SPPs also provide a cost savings component. Baldini (2009-2011)  Another factor that may be considered when selecting a formulary product is an MCO's ability to drive utilization to those products. When all factors are otherwise equal, some manufacturers may offer rebates based on formulary placement. Placing step-therapy protocols on nonpreferred products would require patients to try preferred products first. Programming this look-back at the point of sale allows for the electronic, realtime review of the member's claim history for evidence of use of first-line agents. In addition, with the increasing utilization of electronic prescribing, this represents another resource to drive formulary product prescribing by providers. Electronic prescribing has the ability to notify the provider when a medication is nonformulary, requires step therapy or prior authorization, allowing the provider to intervene prior to the patient leaving the office.

AWP Cost a for MS Medications
Many formulary management tactics are utilized by MCOs to manage costs of DMTs. However, one component that MCOs cannot control is manufacturer price increases. In the 4 months prior to fingolimod's (Gilenya) release, all MS products had an increase in the average wholesale price (AWP).  Figure 1.
The Medco 2011 Drug Trend Report for 2010 data reported 9.4% inflation for all brand drugs. 96 The average percent change in AWP for MS products from 2009 to 2010 was 16.4%, with a maximum of 28.2% and a minimum change of 8.0%. 96 This is a clear illustration that price increases for DMTs and specialty drugs outpaced price increases for brand medications. The price increases for specific medications for 3 years through September 2011 are shown in Table 3. 96 The average unit prices for MS agents will likely continue to rise at a rate higher than the unit price increases of other brand drugs because new oral agents for MS are likely to benchmark their prices against Gilenya. 96 In addition to managing MS patients through case or disease management programs within an SPP or MCO, another point of contact for these patients is through the Medicare medication therapy management programs (MTMP). This allows coordination of medication management with providers, members, and disease management programs. Medicare  Part D sponsors utilize the CMS criteria in identifying beneficiaries for the MTMP. Targeted beneficiaries include those with multiple chronic diseases (sponsors cannot require more than 3 chronic diseases as the minimum) who are taking multiple Part D drugs (sponsors cannot require more than 8 Part D drugs as the minimum number) and are likely to incur annual costs of at least $3,100.20 in 2012. A Comprehensive Medication Review (CMR) performed by a clinical pharmacist will be completed for all members who qualify for the program who do not opt out. A letter summarizing the CMR is provided to the member's physician and, if it was a live review, provided to the member. The CMR encourages the physician to review the clinical pharmacist's recommendations, which typically includes interpreting, monitoring, and assessing the member's laboratory and test results; assessing, identifying, and prioritizing medication-related problems concerning the dose and dosing regimen of each medication; and considering other therapy-related issues, such as adherence to therapy, medication cost considerations, and drug interactions or side effects. As a result of the above analysis of the member's medications, the physician may intervene on recommendations made in the CMR resulting in improved safety and efficacy for the member and decreased costs for the MCO.

Managed Approaches to Multiple Sclerosis in Special Populations
Because there are no DMTs available in the generic form at this time and the potential addition of 3 new oral medications in the near future, MCOs will continue to have challenges managing the direct costs associated with the treatment of MS. Formulary management tools, SPPs, case management and disease management programs, and MTMP will continue to provide resources to manage utilization and costs associated with this class of medications.

■■ Summary
The health economics of MS are a central issue for MCOs managing Medicaid beneficiaries. Management of MS can be tangibly impacted by the myriad of symptoms found in MS patients, long-term treatment-associated costs, and the complexity of the treatment and management needs of this patient population. A number of new agents, including more oral drugs expected to become available in the near future, bring promise but are anticipated to increase the cost of MS care. The benefitrisk profile of these new agents will need to be considered in the context of established first-line parenteral drugs and communicated to patients and providers. Current lack of treatment guidelines in MS can make it difficult to mitigate economic risk in special populations without algorithms to guide decision making. Case management and collaborative practice models that engage SPPs, MTMPs, and other tools in managed care can provide outcomes-based interventions aimed at controlling costs while maximizing treatment efficacy.